S-(N-methylcarbamoyl)glutathione: a reactive S-linked metabolite of methyl isocyanate.
S-(N-methylcarbamoyl)glutathione, a chemically-reactive glutathione conjugate, has been isolated from the bile of rats administered methyl isocyanate and characterized, as its N-benzyloxycarbonyl dimethylester derivative, by tandem mass spectrometry. The ability of this glutathione adduct to donate an N-methylcarbamoyl moiety to the free -SH group of cysteine was evaluated in vitro with the aid of a highly specific thermospray LC/MS assay procedure. The glutathione adduct reacted readily with cysteine in buffered aqueous media (pH 7.4, 37 degrees C) and after 2 hr, 42.5% of the substrate existed in the form of S-(N-methylcarbamoyl)cysteine. The reverse reaction, i.e. between the cysteine adduct and free glutathione, also took place readily under these conditions. It is concluded that conjugation of methyl isocyanate with glutathione in vivo affords a reactive S-linked product which displays the potential to carbamoylate nucleophilic amino acids. The various systemic toxicities associated with exposure of animals or humans to methyl isocyanate could therefore be due to release of the isocyanate from its glutathione conjugate, which thus may serve as a vehicle for the transport of methyl isocyanate in vivo.
Pearson
P G
PG
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Slatter
J G
JG
Rashed
M S
MS
Han
D H
DH
Grillo
M P
MP
Baillie
T A
TA
D000818:Animals; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D003485:Cyanates / Q000378:metabolism*; D003545:Cysteine; D005978:Glutathione / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000302:isolation & purification; D017953:Isocyanates; D007700:Kinetics; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D011919:Rats, Inbred Strains
D003485:Cyanates; D017953:Isocyanates; C053323:S-(N-methylcarbamoyl)glutathione; C008461:methyl isocyanate; D005978:Glutathione; D003545:Cysteine